TALK-1 channels control ? cell endoplasmic reticulum Ca2+ homeostasis.

ABSTRACT: Ca2+ handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic ? cell function and becomes perturbed during the pathogenesis of diabetes. ER Ca2+ homeostasis is determined by ion movements across the ER membrane, including K+ flux through K+ channels. We demonstrated that K+ flux through ER-localized TALK-1 channels facilitated Ca2+ release from the ER in mouse and human ? cells. We found that ? cells from mice lacking TALK-1 exhibited reduced basal cytosolic Ca2+ and increased ER Ca2+ concentrations, suggesting reduced ER Ca2+ leak. These changes in Ca2+ homeostasis were presumably due to TALK-1-mediated ER K+ flux, because we recorded K+ currents mediated by functional TALK-1 channels on the nuclear membrane, which is continuous with the ER. Moreover, overexpression of K+-impermeable TALK-1 channels in HEK293 cells did not reduce ER Ca2+ stores. Reduced ER Ca2+ content in ? cells is associated with ER stress and islet dysfunction in diabetes, and islets from TALK-1-deficient mice fed a high-fat diet showed reduced signs of ER stress, suggesting that TALK-1 activity exacerbated ER stress. Our data establish TALK-1 channels as key regulators of ? cell ER Ca2+ and suggest that TALK-1 may be a therapeutic target to reduce ER Ca2+ handling defects in ? cells during the pathogenesis of diabetes.

SUBMITTER: Vierra NC 

PROVIDER: S-EPMC5672804 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature